U.S. Pat. No. 3,652,589 discloses a genus of phenol ethers, which are described as having analgesic properties. The genus includes (1R,2R or 1S,2S)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-cyclohexanol), which has been given the generic name “tramadol.” Tramadol (marketed as the HCl salt) is a synthetic atypical, centrally-acting opioid analgesic used for treating moderate to severe pain with efficacy and potency ranging between weak opioids and highly potent opioids such as morphine (Raffa et al., 1992, J Pharmacol Exp Ther,. 260:275-85).
Tramadol was developed by the German pharmaceutical company Grunenthal GmbH in the late 1970s under the trade name TRAMAL®. One of the advantages of tramadol over traditional opioids is its lower risk of opioid dependence, resulting in it having an unscheduled status in the U.S. and other countries. (Raffa, 2008, J Clin Pharm Ther, 33:101-08).
Tramadol is a racemate consisting of 1R,2R-tramadol [(+)-tramadol], and 1S,2S-tramadol [(−)-tramadol]. After oral administration of the racemate, both the (−) and (+) forms of both tramadol and the M1 metabolite (i.e., both the 1R,2R-isomer and 1S,2S-isomer of O-desmethyltramadol) are detected in the circulation.
At least two synergistic mechanisms appear operative in providing analgesic activity: binding to μ-opioid receptors and inhibition of reuptake of norepinephrine and serotonin. (Raffa 1992). The monoaminergic activity of the parent makes a significant contribution to analgesia by blocking nociceptive impulses at the spinal level.
Consistent with non-opioid mechanisms of analgesia, tramadol induced analgesia is only partially antagonized by the opiate antagonist naloxone in animals and humans (Raffa 1992; Kayser et al. 1991, Eur J Pharmacol, 195:37-45; Kayser et al., 1992, Eur J Pharmacol, 224:83-8; Collart et al., 1993, Br J Clin Pharmacol, 35:73P). Likewise, in a double-blind, placebo-controlled, crossover study in volunteers, tramadol analgesia was reduced by more than half by an adrenergic receptor antagonist, consistent with tramadol's non-opioid analgesic mechanism involving inhibition of neuronal uptake of norepinephrine (Desmeules et al., 1996, Br J Clin Pharmacol, 41:7-12).
This dual and synergistic mechanism of action is further attributed to complementary and interactive, mechanisms of action of each tramadol enantiomer. The (+)-enantiomer of tramadol exhibits a 10-fold higher analgesic activity due to a greater affinity for the μ-receptor and is a more effective inhibitor of serotonin reuptake, while the (−)-enantiomer is a more effective inhibitor of noradrenalin reuptake and increases noradrenaline release by auto receptor activation. (Raffa et al., 1993, J Pharmacol Exp Ther, 267:331-40).
In addition to treating pain, tramadol and O-desmethyltramadol are said to be effective for treating premature ejaculation (U.S. Pat. No. 6,974,839) and urinary incontinence (U.S. Pat. No. 6,660,774), and each as their single (−) enantiomer are said to be effective for the prevention or treatment of nausea and vomiting (U.S. Pat. No. 6,297,286). Tramadol itself is said to be effective for treating coughs, inflammatory and allergic reactions, depression, obsessive-compulsive spectrum disorders, drug and/or alcohol abuse, gastritis, diarrhea, cardiovascular disease, respiratory disease, mental illness and/or epilepsy (U.S. Pat. Nos. 6,387,956 and 6,723,343 and Rojas-Corrales et al., 1998, Life Sciences, 63).
Resistance to Tramadol Analgesia
Tramadol is rapidly and extensively metabolized in the liver. The principal metabolic pathways involve cytochrome P-450 isoenzymes 2D6 and 2B6 (O-desmethylation) and 3A4 (N-desmethylation). Importantly, production of both enantiomers of M1 (i.e., 1R,2R-O-desmethyltramadol or “(+)-M1”, and 1S,2S-O-desmethyltramadol or “(−)-M1”) is dependent on the polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Approximately 10% of Caucasians have a genotype resulting in reduced activity of CYP2D6. These individuals are poor metabolizers (PM) of tramadol, and they exhibit resistance to tramadol analgesia and diminished or absent M1 in their blood (Kirchheiner et al., 2008, J Clin Psychopharmacol, 28:78-83).
Several human clinical studies have shown that tramadol efficacy is significantly decreased or lacking in PM patients. In the first study, using two parallel, randomized, double-blind, placebo-controlled crossover designs, the analgesic effect of tramadol was assessed in 27 volunteers (fifteen extensive metabolizers “Ems” and twelve PMs) using several experimental pain models (Poulsen et al., 1996, Clin Pharmacol Ther, 60:636-44). Differences existed between EMs and PMs that indicated M1 was critical for a portion of the analgesic effect of tramadol.
In the second study, the effect of CYP450-2D6 polymorphism on tramadol analgesia was assessed in 300 Caucasian patients undergoing major abdominal surgery (Stamer et al., 2003, Pain,. 105:231-38). Patients who had one or more functional alleles were classified as EMs. Genotyping revealed that 35 patients were PMs. Compared to the EMs, the PMs displayed a significantly higher incidence of non-response (P=0.005) and required more tramadol or rescue medication (P=0.02).
In the third study, the effect of CYP450-2D6 polymorphism (specifically CYP450-2D6*10, a SNP (single nucleotide polymorphism) that results in a Pro34 to Ser substitution and reduced CYP450-2D6 metabolic activity) on tramadol-induced analgesia (administered via PCA) was assessed in 63 Chinese patients who underwent gastrectomy for gastric cancer (Wang et al., 2006, Eur J Clin Pharmacol, 62:927-31). The patients were classified as EMs (N=17) or either heterozygous (N=26) or homozygous (n=20) for CYP2D6*10. Compared to the other groups, the homozygous group required more tramadol (P<0.05).
Finally, a fourth study of patients (N=187) undergoing major abdominal surgery reported a 4-fold greater non-response rate to tramadol in CYP450-2D6 poor metabolizers (Stamer et al., 2007, Clin Pharmacol Ther, 82:41-47). In summary, for mild to moderate pain, both opioid and non-opioid components of tramadol contribute to analgesia. The analgesic effect of tramadol is decreased or absent in patients who have low CYP450-2D6 enzymatic activity (CYP450-2D6, “poor metabolizers” or PMs) because their M1 serum concentration is considerably less than that in other genotypes.
Sensitivity to the Adverse Events of Tramadol
Approximately 2% of northern white European, and 7% of southern Europeans carry the CYP2D6 gene duplication (more than two functional alleles) that results in ultra-rapid metabolism of tramadol, and these ultra-rapid metabolizers (UMs) are more sensitive to the adverse events of tramadol than other genotypes (Kirchheiner 2008). In particular, the pharmacokinetics and effects were monitored after a single dose of 100 mg racemic tramadol in 11 UMs and 11 EMs (i.e., two active alleles). Almost 50% of the UM group experienced nausea compared with only 9% of the EM group.
M1 Metabolite (O-Desmethyltramadol)
Potschka dosed female Wistar rats (intraperitoneal) with the (+)-M1 enantiomer followed by observation for adverse effects (Potschka et al., 2000, Br J Pharmacol, 131:203-12). Garrido dosed male Sprague-Dawley rats i.v. (intravenous) with the (+)-M1 enantiomer alone, or (+)-M1 together with the (−)-M1 enantiomer (Garrido et al., 2000, J Pharmacol Exp Ther, 295:352-59). KuKanich administered i.v. racemic M1 to beagle dogs (KuKanich et al., 2004, J Vet Pharmacol Ther, 27:239-46).